The studies proposed in this application are designed to identify and evaluate biochemical parameters that may aid in the understanding of the basis for selective action of antimetabolites. These studies will be carried out in vivo using mouse leukemia cells sensitive and resistant to arabinosylcytosine and 5-fluorinated pyrimidines. Other agents will include 3-deazauridine, 2-azido and 2'amino-ara-C. These studies include: 1) Drug uptake, activation and incorporation into nucleic acids: 2) Intracellular retention of ara-CTP and 5-FdUMP in tumors and normal tissues; 3) degree of utilization of normal and malignant cells of de novo and salvage metabolites and possible relationship between these results and ribonucleotide pools and their ratios. Furthermore, the role of normal metabolites in the modification of the therapeutic index of 5-FU in mouse and rat colon tumors will be evaluated. Studies will also be carried out to determine whether or not liposome encapsulated drug can be used to overcome resistance and/or to modify the selective toxicity of antimetabolites. Therefore, this research proposal represents an integrated multifactorial approach in which various biochemical and pharmacological parameters will be measured and integrated to produce a profile predictive for response in individual tumor types and to provide a rationale for the design of specific chemotherapy with available drugs and metabolites, alone or in combination.